The 70-kDa heat shock protein chaperone nucleotide-binding domain in solution unveiled as a molecular machine that can reorient its functional subdomains

Proceedings of the National Academy of Sciences of the United States of America
Yongbo Zhang, Erik R P Zuiderweg

Abstract

The 70-kDa heat shock cognate (Hsc70) chaperone plays a crucial role in protein (re-)folding and triage in the mammalian cytosol. Here we study, by NMR, the 44-kDa nucleotide-binding domain (NBD) of this molecule, which allosterically regulates, by binding either ADP or ATP in a cleft between the two main lobes, the chaperoning affinity of the attached substrate-binding domain. The NBD is also a center of interaction with cochaperones that couple into the allostery. By measuring residual dipolar couplings by NMR, we show that the orientation of two lobes of the Hsc70 NBD in solution deviates up to 10 degrees from their positions in 14 superimposing x-ray structures. Additional orientational differences of subdomains within the lobes unveil the Hsc70 NBD in solution as a flexible molecular machine that can adjust the relative positions of all of its four subdomains. Because the residues interacting with the nucleotide emanate from all four subdomains, adjustments in subdomain orientation should affect the nucleotide chemistry and vice versa. Our data suggest a hypothesis that cochaperone or substrate domain binding perturbs the relative subdomain orientations, thereby functionally and allosterically coupling to the nucleotide st...Continue Reading

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